Glycine is one of inhibitory neurotransmitters. Glycine shows an inhibitory activity on sensory nerves through strychnine-sensitive glycine receptors (ssGlyRs) in the spinal cord and the brain stem of a vertebrate.
It has been reported that a pain threshold is elevated by intrathecal administration of glycine, while it is lowered by intrathecal administration of strychnine having a glycine receptor antagonistic activity. Those results suggest that a pain threshold may be kept at a certain level or higher by stimulation of strychnine-sensitive glycine receptors by glycine in the spinal cord.
On the other hand, for many neurotransmitters, there are reuptake systems into cells. Specific transporters are participated in those reuptake systems, whereby concentration of the neurotransmitter is controlled.
As glycine-specific transporters, there have been known two classes such as glycine transporter type 1: GlyT1 (including subtypes: GlyT1a, GlyT1b, GlyT1c) and glycine transporter type 2: GlyT2 (including subtypes: GlyT2a, GlyT2b), and genes thereof were cloned one after another in the 1990s [Guastella et al., Proc. Natl. Acad. Sci. USA, 1992, 89, 7189; Liu et al., FEBS Lett., 1992, 305, 110; Smith et al., Neuron, 1992, 8, 927; Borosky et al., Neuron, 1993, 10, 851].
Among these transporters for glycine, GlyT1 is widely distributed in the central nervous system: CNS, and existing mainly in glia cells and it has been considered that GlyT1 has a role to maintain a low concentration of glycine in an extracellular fluid.
On the contrary, GlyT2 exists locally in the brain stem and the spinal cord. GlyT2 takes a role in the reuptake system of glycine acting as a neurotransmitter in the brain stem and the spinal cord, and removes glycine from a synaptic space and inactivates glycinergic neuro-activity. Further, GlyT2 has the same distribution pattern as strychnine-sensitive glycine receptor: ssGlyR, and closely relates to the inhibitory system through strychnine-sensitive glycine receptors. Based upon this knowledge, it has been considered that the synaptic glycine level in the intrathecal space is elevated by inhibition of GlyT2 activity, and whereby the function of inhibitory neuron expressing ssGlyR is activated and then pain-related neurotransmission should be limited. Further, compounds which inhibit the transporting activity of GlyT2 (GlyT2 inhibitor) have been considered as being useful as a muscle relaxant, an anesthetic, an analgesic, etc. for treatment of muscle spasticity, tinnitus, epilepsy, neuropathic pain, etc. [Isaac et al., Bioorg. Med. Chem. Lett. 2001, 11, 1371-1373; WO2003/1013-2 (Akzo Nobel); Caulfield et al., J. Med. Chem., 2001, 44: 2679-2682; Ho et al., Bioorganic & Medicinal Chemistry Letters, 2004, 14, 545-548; Friauf et al., J. Comp. Neurol., 1999, 412, 17; Simpson et al., Neurochem. Res., 1996, 21, 1221; Huang et al., Neurol. Res., 2000, 22, 160; Gomeza et al., Curr. Opin. Drug Discovery Dev., 2003, 6, 675; Aragon., Eur. J. Pharmacol., 2003, 479, 249-262].
Further, it has actually been reported that a compound which inhibits the transporting activity of GlyT2 (GlyT2 inhibitor) shows an effect of improving hyperalgesia by increasing a pain threshold in neuropathic pain models [Houghton et al., 31st Society of Neuroscience Meeting Abstracts 2001, 27 (Abs 283.1)].
Further, GlyT2 inhibitors are considered as being useful for treatment of urological disorders [WO 2005/94808 (Bayer Healthcare)].
Consequently, GlyT2 inhibitors have been expected to be developed as an excellent medicament. Particularly, neuropathic pain syndromes are difficult to be cured, and available medicaments for neuropathic pain such as μ-Opioid, etc. often show side effects to the central nervous system, and thus, it has strongly been demanded to develop an excellent medicament therefor.
As to compounds which inhibit the transportation activity of GlyT2 (GlyT2 inhibitor), the following reports have been found.
For instance, amino acid derivatives having GlyT2 inhibiting activity are disclosed in the literature of Isaac et al. (Isaac et al, Bioorg. Med. Chem. Lett. 2001, 11, 1371-1373) (NPS); benzamide derivatives such as N-[(1-dimethylaminocycloalkyl)methyl]benzamide derivatives, 2-(aminomethyl)benzamide derivatives, etc. are disclosed in WO 2003/10132 (Akzo Nobel), the literature of Caulfield et al. (Caulfield et al., Journal of Medicinal Chemistry, 2001, 44, 2679-2682) and the literature of Ho et al. (Ho et al., Bioorganic & Medicinal Chemistry Letters, 2004, 14, 545-548).
Further, α, β and γ amino acid derivatives are disclosed in the literatures of Wolin et al. (Wolin et al., Bioorganic & Medicinal Chemistry, 2004, 12:4477-4492; Wolin et al., Bioorganic & Medicinal Chemistry, 2004, 12:4493-4509) and WO 2005/044810 (Janssen Pharmaceutica).
Still further, aryl piperidine amide derivatives are disclosed in the literatures of Wolin et al. (Wolin et al., Bioorganic & Medicinal Chemistry, 2004, 12:4511-4532) and WO 2005/021525 (Janssen Pharmaceutica).